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Emerging evidence shows correlation between the presence of neutralization antibodies (nAbs) and protective immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently available commercial serology assays lack the ability to specifically identify nAbs. An enzyme-linked immunosorbent assay-based nAb assay (GenScript cPass neutralization antibody assay) has recently received emergency use authorization from the Food and Drug Administration. To evaluate the performance characteristics of this assay and compare and correlate it with the commercial assays that detect SARS-CoV-2-specific immunoglobulin G (IgG). Specimens from SARS-COV-2 infected patients (n = 124), healthy donors obtained prepandemic (n = 100), and patients with non-coronavirus disease 2019 (COVID-19) respiratory infections (n = 92) were analyzed using this assay. Samples with residual volume were also tested on 3 commercial serology platforms (Abbott, Euroimmun, Siemens). Twenty-eight randomly selected specimens from patients with COVID-19 and 10 healthy controls were subjected to a plaque reduction neutralization test. The cPass assay exhibited 96.1% (95% CI, 94.9%-97.3%) sensitivity (at >14 days post-positive PCR), 100% (95% CI, 98.0%-100.0%) specificity, and zero cross-reactivity for the presence of non-COVID-19 respiratory infections. When compared with the plaque reduction assay, 97.4% (95% CI, 96.2%-98.5%) qualitative agreement and a positive correlation (R2 = 0.76) was observed. Comparison of IgG signals from each of the commercial assays with the nAb results from plaque reduction neutralization test/cPass assays displayed greater than 94.7% qualitative agreement and correlations with R2 = 0.43/0.68 (Abbott), R2 = 0.57/0.85 (Euroimmun), and R2 = 0.39/0.63 (Siemens), respectively. The combined data support the use of cPass assay for accurate detection of the nAb response. Positive IgG results from commercial assays associated reasonably with nAbs presence and can serve as a substitute.

Some serology assays demonstrated useful for post-treatment monitoring of Strongyloides stercoralis infection. Serology frequently has low specificity, which might be improved by the use of recombinant antigens. The Strongy Detect ELISA is based on 2 recombinant antigens (SsIR and NIE) and proved good accuracy. Aim of this study was to evaluate the performance of this test for the post-treatment monitoring of strongyloidiasis. We tested 38 paired sera, with matched fecal tests results, stored in our biobank and originating from a randomized controlled trial. At baseline, all patients tested positive for at least 1 fecal assay among PCR, direct stool microscopy and agar plate culture. Patients were re-tested with both serology and fecal assays 12 months after treatment. Primary outcome was the relative reduction in optical density (OD) between baseline and follow up. We observed that about 95% samples showed a reduction between pre and post-treatment OD, with a median relative reduction of 93.9% (IQR 77.3%–98.1%). In conclusion, the test proved reliable for post-treatment monitoring. However, some technical issues, including that the threshold for positivity has not be predefined, and that a substantial number of samples showed overflow signals, need to be fixed to permit use in routine practice.

The natural course of idiopathic pulmonary fibrosis (IPF) is variable. Predicting disease progression and survival in IPF is important for treatment. We previously demonstrated that serum periostin has the potential to be a prognostic biomarker for IPF. Our aim was to use monomeric periostin in a multicenter study to evaluate its efficacy in diagnosing IPF and predicting its progression. To do so, we developed a new periostin kit to detect only monomeric periostin. The subjects consisted of 60 IPF patients in a multicenter cohort study. We applied monomeric periostin, total periostin detected by a conventional kit, and the conventional biomarkers-KL-6, SP-D, and LDH-to diagnose IPF and to predict its short-term progression as estimated by short-term changes of %VC and % DL, CO. Moreover, we compared the fraction ratios of monomeric periostin to total periostin in IPF with those in other periostin-high diseases: atopic dermatitis, systemic scleroderma, and asthma. Monomeric periostin showed the greatest ability to identify IPF comparable with KL-6 and SP-D. Both monomeric and total periostin were well correlated with the decline of %VC and % DL, CO. Clustering of IPF patients into high and low periostin groups proved useful for predicting the short-term progression of IPF. Moreover, the relative ratio of monomeric periostin was higher in IPF than in other periostin-high diseases. Measuring monomeric periostin is useful for diagnosing IPF and predicting its short-term progression. Moreover, the ratio of monomeric periostin to total periostin is elevated in IPF compared to other periostin-high diseases.

The ComFluCOV trial tested the safety and immunogenicity of COVID-19 and influenza vaccines co-administration. Binding and functional SARS-CoV2 anti-spike responses were measured using assays developed in response to the COVID-19 pandemic. The three assays used to measure the immunogenicity outcomes are reported here and their performance compared to inform future vaccine development. Adults aged over 18 were vaccinated with a COVID-19 and either an influenza vaccine or saline placebo. Serum sampled one month after vaccination was used to measure SARS-CoV2 anti-spike antibody concentrations using a commercial in-house enzyme-linked immunosorbent assay (ELISA), a commercial fast throughput electrochemiluminescence immunoassay (ECLIA) and a viral neutralisation assay (VNA). Geometric mean ratios were used to compare the response to COVID-19 with or without influenza vaccine with a threshold of 0.67 considered non-inferior. The relationship between the different assays was examined using Kendall rank correlations. The geometric mean ratios exceeded 0.67 using all assays for all COVID-19 and influenza vaccine combinations tested. Moderate rank correlations were found between the three assays. All three assays confirmed that vaccine co-administration did not significantly impact on immunogenicity of any of the vaccines tested. Trial registration: ISRCTN14391248, registered on 17/03/2021.

Background. The phase III Zostavax Efficacy and Safety Trial of 1 dose of licensed zoster vaccine (ZV; Zostavax; Merck) in 50-59-year-olds showed approximately 70% vaccine efficacy (VE) to reduce the incidence of herpes zoster (HZ). An objective of the trial was to assess immune response biomarkers measuring antibodies to varicella zoster virus (VZV) by glycoprotein-based enzyme-linked immunosorbent assay as correlates of protection (CoPs) against HZ. Methods. The principal stratification vaccine efficacy curve framework for statistically evaluating immune response biomarkers as CoPs was applied. The VE curve describes how VE against the clinical end point (HZ) varies across participant subgroups defined by biomarker readout measuring vaccine-induced immune response. The VE curve was estimated using several subgroup definitions. Results. The fold rise in VZV antibody titers from the time before immunization to 6 weeks after immunization was an excellent CoP, with VE increasing sharply with fold rise: VE was estimated at 0% for the subgroup with no rise and at 90% for the subgroup with 5.26-fold rise. In contrast, VZV antibody titers measured 6 weeks after immunization did not predict VE, with similar estimated VEs across titer subgroups. Conclusions. The analysis illustrates the value of the VE curve framework for assessing immune response biomarkers as CoPs in vaccine efficacy trials. Clinical Trials Registration. NCT00534248.

The plaque reduction neutralization test (PRNT), which measures a subset of immunoglobulin antibodies (functional neutralizing antibodies), and the enzyme-linked immunosorbent assay (ELISA), which measures total immunoglobulin (neutralizing and nonneutralizing antibodies), characterize different aspects of the anti-mumps virus antibody response after vaccination. Data from a recent phase 3 clinical trial (NCT01681992) of 2 measles-mumps-rubella vaccines were used to compare anti-mumps antibody responses measured using an unenhanced PRNT (GSK; seropositivity cutoff and threshold, 2.5 and 4 times the 50% end-point dilution, respectively) with those estimated using an ELISA (thresholds, 5 and 10 ELISA units/mL, respectively). Of 3990 initially seronegative samples, 3284 (82.3%) were seropositive after vaccination for anti-mumps antibodies in both assays. The Pearson correlation coefficient for double-positive samples was 0.57, indicative of a moderate correlation. Receiver operating characteristic curve analysis showed that an ELISA threshold of 51.7 ELISA units/mL best corresponded to the PRNT seroresponse threshold. There was no obvious vaccine brand effect on the correlation between assays. The moderate correlation between the anti-mumps antibody measurements obtained with PRNT and ELISA reflects different aspects of the serological response. In the absence of a well-defined protective serological threshold, PRNT provides complementary information on the antibody response, whereas ELISA remains a critically useful measurement of vaccine immunogenicity.

Background. Accurate diagnosis of malaria infection during pregnancy remains challenging because of low parasite densities and placental sequestration of Plasmodium falciparum. The performance of different methods to detect P. falciparum in pregnancy and the clinical relevance of undetected infections were evaluated. Methods. P. falciparum infections were assessed in 272 Mozambican women at delivery by microscopy, placental histology, quantitative polymerase chain reaction (qPCR) and detection of histidine-rich protein 2 (HRP2) in plasma by enzyme-linked immunosorbent assay (ELISA) and a rapid diagnostic test (RDT). Association between infection and delivery outcomes was determined. Results. Among the 122 women qPCR-positive for P. falciparum in peripheral and/or placental blood samples, 87 (71.3%) did not receive a positive diagnosis by peripheral microscopy, 75 (61.5%) by HRP2 ELISA, and 74 (60.7%) by HRP2 RDT in plasma. Fifty-seven of the 98 qPCR-positive placental infections (58.2%) were not detected by histology. Women who were qPCR-positive but negative in their peripheral blood by microscopy or HRP2 RDT in plasma (n = 62) were at increased risk of anemia, compared with negative women (n = 141; odds ratio, 2.03; 95% confidence interval, 1.07—3.83; P = .029). Conclusions. Microscopy, placental histology and HRP2-based plasma diagnostic methods fail to identify the majority of the P. falciparum infections detected by qPCR in peripheral and placental blood. Undetected infections were associated with maternal anemia, highlighting the urgent need for more accurate malaria diagnostic tools for pregnant women to avoid the negative clinical impact that hidden infections can have during pregnancy. Clinical Trials Registration. NCT00209781.

Objective The detection of autoantibodies is essential to diagnose autoimmune hepatitis (AIH). Particularly in children, specificity of autoantibodies decreases due to lower titers being diagnostic and being present not only in AIH but also in other liver diseases. Recently, quantification of polyreactive IgG (pIgG) for detection of adult AIH showed the highest overall accuracy compared to antinuclear antibodies (ANA), anti-smooth muscle antibodies (anti-SMA), anti-liver kidney microsomal antibodies (anti-LKM) and anti-soluble liver antigen/liver pancreas antibodies (anti-SLA/LP). We aimed to evaluate the diagnostic value of pIgG for pediatric AIH. Design pIgG, quantified using HIP1R/BSA coated ELISA, and immunofluorescence on rodent tissue sections were performed centrally. The diagnostic fidelity to diagnose AIH was compared to conventional autoantibodies of AIH in training and validation cohorts from a retrospective, European multi-center cohort from nine centers from eight European countries composed of existing biorepositories from expert centers ( n  = 285). Results IgG from pediatric AIH patients exhibited increased polyreactivity to multiple protein and non-protein substrates compared to non-AIH liver diseases and healthy children. pIgG had an AUC of 0.900 to distinguish AIH from non-AIH liver diseases. pIgG had a 31–73% higher specificity than ANA and anti-SMA and comparable sensitivity that was 6–20 times higher than of anti-SLA/LP, anti-LC1 and anti-LKM. pIgG had a 21–34% higher accuracy than conventional autoantibodies, was positive in 43–75% of children with AIH and normal IgG and independent from treatment response. Conclusion Detecting pIgG improves the diagnostic evaluation of pediatric AIH compared to conventional autoantibodies, primarily owing to higher accuracy and specificity. Graphical Abstract

Tuberculosis (TB) is a major global health problem and the only currently-licensed vaccine, BCG, is inadequate. Many TB vaccine candidates are designed to be given as a boost to BCG; an understanding of the BCG-induced immune response is therefore critical, and the opportunity to relate this to circumstances where BCG does confer protection may direct the design of more efficacious vaccines. While the T cell response to BCG vaccination has been well-characterized, there is a paucity of literature on the humoral response. We demonstrate BCG vaccine-mediated induction of specific antibodies in different human populations and macaque species which represent important preclinical models for TB vaccine development. We observe a strong correlation between antibody titers in serum versus plasma with modestly higher titers in serum. We also report for the first time the rapid and transient induction of antibody-secreting plasmablasts following BCG vaccination, together with a robust and durable memory B cell response in humans. Finally, we demonstrate a functional role for BCG vaccine-induced specific antibodies in opsonizing mycobacteria and enhancing macrophage phagocytosis in vitro , which may contribute to the BCG vaccine-mediated control of mycobacterial growth observed. Taken together, our findings indicate that the humoral immune response in the context of BCG vaccination merits further attention to determine whether TB vaccine candidates could benefit from the induction of humoral as well as cellular immunity.

ContextGlucagon-like peptide-1 agonists acutely lower serum glucagon. However, in the Liraglutide and β-Cell Repair (LIBRA) Trial, 48-week treatment with liraglutide yielded lower/unchanged fasting glucagon but, surprisingly, enhanced postchallenge glucagonemia [measured by R&D Systems (Minneapolis, MN) assay].ObjectiveBecause differences between glucagon assays potentially could explain these unexpected findings, we have remeasured glucagon in all 1222 samples from this trial using the highly-sensitive/specific Mercodia assay to compare the findings between assays.Design/Setting/Participants/InterventionIn LIBRA, 51 patients with type 2 diabetes of 2.6 ± 1.9 years duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with serial oral glucose tolerance test (OGTT) every 12 weeks (with liraglutide/placebo last administered ∼24 hours earlier).OutcomeSerum glucagon was measured every 30 minutes on each OGTT, enabling determination of the area under the glucagon curve (AUCglucagon).ResultsWith the Mercodia assay, fasting glucagon was higher in the liraglutide arm than placebo at 12 weeks (P = 0.01), with no between-group differences at 24, 36, and 48 weeks. There was no difference in AUCglucagon between the groups at any visit. Mercodia and R&D Systems glucagon measurements correlated at postchallenge time points but not at fasting.ConclusionThe Mercodia assay did not replicate the R&D Systems glucagon findings. Although neither assay demonstrated lower postchallenge glucagonemia with chronic liraglutide last administered ∼24 hours earlier, the differential response reported by these assays precludes definitive conclusion and highlights the critical role of assay selection when measuring glucagon in clinical studies.The Mercodia and R&D Systems assays do not concur in evaluation of the impact of chronic liraglutide therapy on glucagon secretion, highlighting the critical role of glucagon assay differences.